No abstract

Serum immunoglobulin A (IgA) antibodies are readily detected in mice and people, but the mechanisms underlying the induction of serum IgA and its role in host protection remain uncertain. We report that select commensal bacteria induce several facets of systemic IgA-mediated immunity. Exposing conventional mice to a unique but natural microflora that included several members of the Proteobacteria phylum led to T cell-dependent increases in serum IgA levels and the induction of large numbers of IgA-secreting plasma cells in the bone marrow. The resulting serum IgA bound to a restricted collection of bacterial taxa, and antigen-specific serum IgA antibodies were readily induced after intestinal colonization with the commensal bacterium Helicobacter muridarum. Finally, movement to a Proteobacteria-rich microbiota led to serum IgA-mediated resistance to polymicrobial sepsis. We conclude that commensal microbes overtly influence the serum IgA repertoire, resulting in constitutive protection against bacterial sepsis.

Long-lived plasma cells (PC) in the bone marrow (BM) are a critical source of antibodies after infection or vaccination, but questions remain about the factors that control PCs. We found that systemic infection alters the BM, greatly reducing PCs and regulatory T (Treg) cells, a population that contributes to immune privilege in the BM. The use of intravital imaging revealed that BM Treg cells display a distinct behavior characterized by sustained co-localization with PCs and CD11c-YFP+ cells. Gene expression profiling indicated that BM Treg cells express high levels of Treg effector molecules, and CTLA-4 deletion in these cells resulted in elevated PCs. Furthermore, preservation of Treg cells during systemic infection prevents PC loss, while Treg cell depletion in uninfected mice reduced PC populations. These studies suggest a role for Treg cells in PC biology and provide a potential target for the modulation of PCs during vaccine-induced humoral responses or autoimmunity.

Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B-lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naïve B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundance for numerous mTORC1-and Myc-regulated genes. Myc loss compromised plasma cell differentiation for MZ B cells, and reciprocally induced ectopic mTORC1 signaling in follicular B cells enabled division-independent differentiation and plasma cell-affiliated gene expression. We conclude that ongoing in situ Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state that enables rapid division-independent plasma cell differentiation.